1. Field of the Invention
This invention is directed to novel polyacid derivatives of glycopeptide antibiotics and related compounds. This invention is also directed to pharmaceutical compositions containing such glycopeptide derivatives, methods of using such glycopeptide derivatives as antibacterial agents, and processes and intermediates useful for preparing such glycopeptide derivatives.
2. Background
Glycopeptides (e.g., dalbaheptides) are a well-known class of antibiotics produced by various microorganisms (see Glycopeptide Antibiotics, edited by R. Nagarajan, Marcel Dekker, Inc. New York (1994)). These complex multi-ring peptide compounds are very effective antibacterial agents against a majority of Gram-positive bacteria. Although potent antibacterial agents, the glycopeptides antibiotics are not used in the treatment of bacterial diseases as often as other classes of antibiotics, such as the semi-synthetic penicillins, cephalosporins and lincomycins, due to concerns regarding toxicity.
In recent years, however, bacterial resistance to many of the commonly-used antibiotics has developed (see J. E. Geraci et al., Mayo Clin. Proc. 1983, 58, 88-91; and M. Foldes, J. Antimicrob. Chemother. 1983, 11, 21-26). Since glycopeptide antibiotics are often effective against these resistant strains of bacteria, glycopeptides such as vancomycin have become the drugs of last resort for treating infections caused by these organisms. Recently, however, resistance to vancomycin has appeared in various microorganisms, such as vancomycin-resistant enterococci (VRE), leading to increasing concerns about the ability to effectively treat bacterial infections in the future (see Hospital Infection Control Practices Advisory Committee, Infection Control Hospital Epidemiology, 1995, 17, 364-369; A. P. Johnson et al., Clinical Microbiology Rev., 1990, 3, 280-291; G. M. Eliopoulos, European J. Clinical Microbiol., Infection Disease, 1993, 12, 409-412; and P. Courvalin, Antimicrob. Agents Chemother, 1990, 34, 2291-2296).
A number of derivatives of vancomycin and other glycopeptides are known in the art. For example, see U.S. Pat. Nos. 4,639,433; 4,643,987; 4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889. Other derivatives are disclosed in EP 0 802 199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; and in J. Amer. Chem. Soc., 1996, 118, 13107-13108; J. Amer. Chem. Soc., 1997, 119, 12041-12047; and J. Amer. Chem. Soc., 1994, 116, 4573-4590.
Despite the above referenced disclosures, a need currently exists for novel glycopeptide derivatives having effective antibacterial activity and an improved mammalian safety profile. In particular, a need exists for glycopeptide derivatives which are effective against a wide spectrum of pathogenic microorganisms, including vancomycin-resistant microorganisms.
The present invention provides novel polyacid glycopeptide derivatives having highly effective antibacterial activity.
Accordingly, the invention provides a compound of the invention, which is a glycopeptide substituted at the C-terminus with a substituent that comprises two or more (e.g. 2, 3, 4, or 5) carboxy (CO2H) groups; or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof.
Preferably, the substituent is attached to a carbonyl group of the C-terminus to form an amide bond, an ester bond, or a thioester bond. More preferably, the substituent is attached to a carbonyl group of the C-terminus to form an amide bond. More preferably, the substituent comprises two carboxy (CO2H) groups. Preferred substituents at the C-terminus include a nitrogen-linked aspartic acid or a nitrogen-linked glutamic acid.
Certain glycopeptide derivatives were disclosed by A. Malabarba, et al., J. Med. Chem., 1989, 32, 2450-2460. Accordingly, the compounds of the invention may preferably exclude the glycopeptides 1) teicoplanin A2 substituted at the C-terminus with a nitrogen-linked glutamic acid, and 2) teicoplanin aglycon (TD) substituted at the C-terminus with a nitrogen-linked glutamic acid.
Other glycopeptide derivatives are also described in U.S. patent application Ser. No. 09/470,209, filed Dec. 22, 1999. Accordingly, the compounds of the invention may also preferably exclude glycopeptides of formula II: 
a) wherein NR17 is nitrogen-linked aspartic acid; R18 is hydrogen; R19 is hydrogen; R20 is 2-(decylamino)ethyl; and R21 is hydrogen;
b) wherein NR17 is nitrogen-linked aspartic acid; R18 is hydrogen; R19 is hydrogen; R20 is 2-(9-hydroxydecylamino)ethyl; and R21 is hydrogen;
c) wherein R17 is 1,4-dicarboxybutyl; R18 is hydrogen; R19 is hydrogen; R20 is 2-(decylamino)ethyl; and R21 is hydrogen; or
d) wherein NR17 is nitrogen-linked aspartic acid; R18 is hydrogen; R19 is hydrogen; R20 is 2-(decylamino)ethyl; and R21 is xe2x80x94CH2xe2x80x94N-(D-glucamine).
The invention also preferably exclude glycopeptides of formula II:
e) wherein R17 is nitrogen-linked aspartic acid; R18 is hydrogen; R19 is hydrogen; R20 is 2-[4-(4-chlorobenzyloxy)benzylamino]ethyl; and R21 is hydrogen;
f) wherein NR17 is 5-(2-carboxypyrrolidin-1-ylcarbonyl)-5-(2-carboxy-3-phenylpropylamino)pentylamino; R18 is hydrogen; R19 is hydrogen; R20 is 2-(decylamino)ethyl; and R21 is hydrogen;
g) wherein NR17 is nitrogen-linked aspartic acid; R18 is hydrogen; R19 is hydrogen; R20 is 2-(decylamino)ethyl; and R21 is xe2x80x94CH2xe2x80x94Nxe2x80x94(Nxe2x80x94CH3-D-glucamine);
h) wherein NR17 is nitrogen-linked aspartic acid; R18 is hydrogen; R19 is hydrogen; R20 is 2-(decylamino)ethyl; and R21 is N-[2-(2-hydroxyethoxy)ethyl]-aminomethyl; or
i) wherein NR17 is nitrogen-linked aspartic acid; R18 is hydrogen; R19 is hydrogen; R20 is 2-(4-isobutylbenzyl)ethyl; and R21 is N-[2-(2-hydroxyethoxy)ethyl]aminomethyl.
A preferred compound of the invention is a glycopeptide of formula I: 
wherein:
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x; or R1 is a saccharide group optionally substituted with xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, or xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R2 is hydrogen or a saccharide group optionally substituted with xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, or xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R3 is a nitrogen-linked, oxygen-linked, or sulfur-linked substituent comprising two or more carboxy groups;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, xe2x80x94C(O)Rd and a saccharide group optionally substituted with xe2x80x94Raxe2x80x94Yxe2x80x94Rb(Z)x, Rf, xe2x80x94C(O)Rf, or xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R5 is selected from the group consisting of hydrogen, halo, xe2x80x94CH(Rc)xe2x80x94NRcRc, xe2x80x94CH(Rc)xe2x80x94NRcxe2x80x94Re, xe2x80x94CH(Rc)xe2x80x94Rx, xe2x80x94CH(Rc)xe2x80x94NRcxe2x80x94Raxe2x80x94C(xe2x95x90O)xe2x80x94Rx, and xe2x80x94CH(Rc)xe2x80x94NRcxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, xe2x80x94C(O)Rd and a saccharide group optionally substituted with xe2x80x94NRcxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, or R5 and R6 can be joined, together with the atoms to which they are attached, form a heterocyclic ring optionally substituted with xe2x80x94NRcxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, and xe2x80x94C(O)Rd;
R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R10 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; or R8 and R10 are joined to form xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2xe2x80x94, where Ar1 and Ar2 are independently arylene or heteroarylene;
R11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic, or R10 and R11 are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring;
R12 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, xe2x80x94C(O)Rd, xe2x80x94C(NH)Rd, xe2x80x94C(O)NRcRc, xe2x80x94C(O)ORd, xe2x80x94C(NH)NRcRcand xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, or R11 and R12 are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring;
R13 is selected from the group consisting of hydrogen or xe2x80x94OR14;
R14 is selected from hydrogen, xe2x80x94C(O)Rd and a saccharide group;
each Ra is independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;
each Rb is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene, provided Rb is not a covalent bond when Z is hydrogen;
each Rc is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and xe2x80x94C(O)Rd;
each Rd is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
Re is a saccharide group;
each Rf is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic;
Rx is an N-linked amino saccharide or an N-linked heterocyclic;
X1, X2 and X3 are independently selected from hydrogen or chloro;
each Y is independently selected from the group consisting of oxygen, sulfur, xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94NRcxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRcC(O)xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NRcSO2xe2x80x94, xe2x80x94C(O)NRcxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94SO2NRcxe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94P(O)(ORc)Oxe2x80x94, xe2x80x94P(O)(ORc)NRcxe2x80x94, xe2x80x94OP(O)(ORc)Oxe2x80x94, xe2x80x94OP(O)(ORc)NRcxe2x80x94, xe2x80x94OC(O)Oxe2x80x94, xe2x80x94NRcC(O)Oxe2x80x94, xe2x80x94NRcC(O)NRcxe2x80x94, xe2x80x94OC(O)NRcxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94 and xe2x80x94NRcSO2NRcxe2x80x94;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
n is 0, 1 or 2; and
x is 1 or 2;
or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof.
Preferably, R1 is a saccharide group optionally substituted with xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z). More preferably R1 is an amino saccharide group substituted on the saccharide nitrogen with xe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)9CH3; xe2x80x94CH2CH2CH2xe2x80x94NHxe2x80x94(CH2)8CH3; xe2x80x94CH2CH2CH2CH2xe2x80x94NHxe2x80x94(CH2)7CH3; xe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)9CH3; xe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)11CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)10CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)8CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)3xe2x80x94CHxe2x95x90CHxe2x80x94(CH)2)4CH3(trans); xe2x80x94CH2CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)7CH3; xe2x80x94CH2CH2xe2x80x94S(O)xe2x80x94(CH2)9CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)6Ph; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2CH2xe2x80x94NHxe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2xe2x80x94NHxe2x80x94CH2-4-[4-(CH3)2CHCH2xe2x80x94]-Ph; xe2x80x94CH2CH2xe2x80x94NHxe2x80x94CH2-4-(4-CF3-Ph)-Ph; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2xe2x80x94S(O)xe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94CH2-4-(3,4-di-Cl-PhCH2Oxe2x80x94)-Ph; xe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94CH2-4-[4-(4-Ph)-Ph]-Ph; xe2x80x94CH2CH2CH2xe2x80x94NHSO2xe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94NHSO2xe2x80x94CH2-4-(Ph-Cxe2x89xa1Cxe2x80x94)-Ph; xe2x80x94CH2CH2CH2xe2x80x94NHSO2-4-(4-Cl-Ph)-Ph; or xe2x80x94CH2CH2CH2xe2x80x94NHSO2-4-(naphth-2-yl)-Ph. Preferably R1 is also an amino saccharide group substituted on the saccharide nitrogen with a 4-(4-chlorophenyl)benzyl group or with a 4-(4-chlorobenzyloxy)benzyl group.
R1 can also be a saccharide group of the formula: 
wherein R15 is xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, or xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x; and R16 is hydrogen or methyl.
Preferably, R2 is hydrogen.
Preferably, the substituent R3 is attached to the C-terminus to form an amide bond, an ester bond, or a thioester bond. More preferably, R3 is attached to the C-terminus to form an amide bond. More preferably, the substituent R3 comprises two carboxy (CO2H) groups. Preferred R3 substituents include a nitrogen-linked aspartic acid or a nitrogen linked glutamic acid.
Preferably, R3 can also be a nitrogen-linked radical of formula III: 
wherein Rg is a saccharide group. More preferably, Rg is Nxe2x80x94(N-methyl-D-glucamine) or N-(D-glucosamine).
Preferably, R4, R6 and R7 are each independently selected from hydrogen or xe2x80x94C(O)Rd. More preferably, R4, R6 and R7 are each hydrogen.
Preferably R5 is hydrogen, xe2x80x94CH2xe2x80x94NHRc, xe2x80x94CH2xe2x80x94NRcRe or xe2x80x94CH2xe2x80x94NHxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x. R5 can also preferably be hydrogen; xe2x80x94CH2xe2x80x94Nxe2x80x94(Nxe2x80x94CH3-D-glucamine); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)9CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHC(O)xe2x80x94(CH2)3COOH; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)9CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94COOH; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)5COOH; xe2x80x94CH2-(morpholin-4-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2CH2OH; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH(OH)xe2x80x94CH2OH; xe2x80x94CH2xe2x80x94N[CH2CH2OH]2; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)3xe2x80x94N(CH3)2; xe2x80x94CH2xe2x80x94N[(CH2)3xe2x80x94N(CH3)2]2; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)3-(imidazol-1-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)3-(morpholin-4-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)4xe2x80x94NHC(NH)NH2; xe2x80x94CH2xe2x80x94Nxe2x80x94(2-amino-2-deoxygluconic acid); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)11CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH(COOH)CH2COOH; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)7CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)8CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)9CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)11CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)7CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2CH2OH; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2C(O)xe2x80x94N-(D-glucosamine); xe2x80x94CH2xe2x80x94NH-(6-oxo-[1,3]oxazinan-3-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)7CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)11CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)6Ph; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)10Ph; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94CH2-(4-(4-CF3-Ph)Ph); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)11CH3; or xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)5xe2x80x94COOH;.
Preferably, R8 is xe2x80x94CH2C(O)NH2, xe2x80x94CH2COOH, benzyl, 4-hydroxyphenyl or 3-chloro-4-hydroxyphenyl.
Preferably, R9 is hydrogen or alkyl.
Preferably, R10 is alkyl or substituted alkyl. More preferably, R10 is the side-chain of a naturally occurring amino acid, such as isobutyl.
Preferably, R11 is hydrogen or alkyl.
Preferably, R12 is hydrogen, alkyl, substituted alkyl or xe2x80x94C(O)Rd. R12 can also preferably be hydrogen; xe2x80x94CH2COOH; xe2x80x94CH2xe2x80x94[CH(OH)]5CH2OH; xe2x80x94CH2CH(OH)CH2OH; xe2x80x94CH2CH2NH2; xe2x80x94CH2C(O)OCH2CH3; xe2x80x94CH2-(2-pyridyl); xe2x80x94CH2xe2x80x94[CH(OH)]4COOH; xe2x80x94CH2-(3-carboxyphenyl); (R)xe2x80x94C(O)CH(NH2)(CH2)4NH2; xe2x80x94C(O)Ph; xe2x80x94C(O)CH2NHC(O)CH3; E-CH2CH2xe2x80x94Sxe2x80x94(CH2)3CHxe2x95x90CH(CH2)4CH3; or xe2x80x94C(O)CH3.
Preferably, X1 and X2 are each chloro.
Preferably, X3 is hydrogen.
Preferably each Y is independently selected from the group consisting of oxygen, sulfur, xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94NRcxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRcC(O)xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NRcSO2xe2x80x94, xe2x80x94C(O)NRcxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94SO2NRcxe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94P(O)(ORc)Oxe2x80x94, xe2x80x94P(O)(ORc)NRcxe2x80x94, xe2x80x94OP(O)(ORc)Oxe2x80x94, xe2x80x94OP(O)(ORc)NRcxe2x80x94, xe2x80x94OC(O)Oxe2x80x94, xe2x80x94NRcC(O)Oxe2x80x94, xe2x80x94NRcC(O)NRcxe2x80x94, xe2x80x94OC(O)NRcxe2x80x94 and xe2x80x94NRcSO2NRcxe2x80x94;
Preferably, n is 0 or 1, and more preferably, n is 1.
Another preferred compound of the invention is a glycopeptide of formula II: 
wherein:
R17 is a dicarboxy-substituted alkyl group having from 3 to 10 carbon atoms;
R18 is selected from the group consisting of hydrogen and alkyl;
R19 is hydrogen;
R20 is xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R21 is hydrogen;
Ra is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;
Rb is selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene, provided Rb is not a covalent bond when Z is hydrogen;
Y is selected from the group consisting of sulfur, xe2x80x94S(O)xe2x80x94 and xe2x80x94SO2xe2x80x94;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic; and
x is 1 or 2;
or a pharmaceutically acceptable salt, or stereoisomer, or prodrug thereof.
For a compound of formula II, Ra is preferably selected from alkylene having from 1 to 10 carbon atoms. For example, Ra can be ethylene (xe2x80x94CH2CH2xe2x80x94), propylene (xe2x80x94CH2CH2CH2xe2x80x94) or butylene (xe2x80x94CH2CH2CH2CH2xe2x80x94).
For a compound of formula II, Z is preferably hydrogen and Rb is alkylene of from 8 to 12 carbon atoms. More preferably, Rb can be a covalent bond, methylene, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)8xe2x80x94, xe2x80x94(CH2)9xe2x80x94 or xe2x80x94(CH2)10xe2x80x94. Additionally, Rb and Z can preferably form an n-octyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl group.
For a compound of formula II, Z is preferably aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic, and Rb is a covalent bond or alkylene of from 1 to 10 carbon atoms. More preferably, Z can be aryl. Preferred aryl groups include phenyl, substituted phenyl, biphenyl, substituted biphenyl and terphenyl groups. Most preferably, Z can be phenyl, 4-isobutylphenyl, 4xe2x80x2-chlorobiphenyl-4-yl, 4xe2x80x2-trifluoromethylbiphenyl-4-yl, 4-(naphth-2-yl)phenyl, 4-(2-phenylethynyl)phenyl, 4-(3,4-dichlorobenzyloxy)-phenyl, or p-terphenyl.
For a compound of formula II, x is preferably 1.
For a compound of formula II, Y is preferably sulfur.
For a compound of formula I or II, xe2x80x94Raxe2x80x94Yxe2x80x94Rb xe2x80x94(Z)x is preferably selected from the group consisting of: xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)10CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)8CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)3xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)4CH3 (trans); xe2x80x94CH2CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)7CH3; xe2x80x94CH2CH2xe2x80x94S(O)xe2x80x94(CH2)9CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)6Ph; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2xe2x80x94S(O)xe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94S(O)xe2x80x94CH2-4-(4-Cl-Ph)-Ph; and xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94CH2-4-[3,4-di-Cl-PhCH2Oxe2x80x94)-Ph. More preferably, xe2x80x94Raxe2x80x94Yxe2x80x94Rb(Z)x is xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3.
For a compound of formula II, R17 is preferably a dicarboxy-substituted alkyl group having from 4 to 6 carbon atoms. More preferably R17 is xe2x80x94CH2(COOH)CH2COOH or xe2x80x94CH2(COOH)CH2CH2COOH. Most preferably, R17 is xe2x80x94CH2(COOH)CH2COOH.
For a compound of formula II, R18 is preferably hydrogen.
A preferred compound of formula II is a compound wherein xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x is xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; R17 is xe2x80x94CH2(COOH)CH2COOH; and R18 is hydrogen.
A preferred value for R15, R20, or xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x is xe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)9CH3; xe2x80x94CH2CH2CH2xe2x80x94NHxe2x80x94(CH2)8CH3; xe2x80x94CH2CH2CH2CH2xe2x80x94NHxe2x80x94(CH2)7CH3; xe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)9CH3; xe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)11CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)10CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)8CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)3xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)4CH3(trans); xe2x80x94CH2CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)7CH3; xe2x80x94CH2CH2xe2x80x94S(O)xe2x80x94(CH2)9CH3; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)6Ph; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2CH2xe2x80x94NHxe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2xe2x80x94NHxe2x80x94CH2-4-[4-(CH3)2CHCH2xe2x80x94]-Ph; xe2x80x94CH2CH2xe2x80x94NHxe2x80x94CH2-4-(4-CF3-Ph)-Ph; xe2x80x94CH2CH2xe2x80x94Sxe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2xe2x80x94S(O)xe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94S(O)xe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94Sxe2x80x94CH2-4-[3,4-di-Cl-PhCH2Oxe2x80x94)-Ph; xe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94CH2-4-[4-(4-Ph)-Ph]-Ph; xe2x80x94CH2CH2CH2xe2x80x94NHSO2xe2x80x94CH2-4-(4-Cl-Ph)-Ph; xe2x80x94CH2CH2CH2xe2x80x94NHSO2xe2x80x94CH2-4-(Ph-Cxe2x89xa1Cxe2x80x94)-Ph; xe2x80x94CH2CH2CH2xe2x80x94NHSO2-4-(4-Cl-Ph)-Ph; or xe2x80x94CH2CH2CH2xe2x80x94NHSO2-4-(naphth-2yl)-Ph. Another preferred value for R15 or R20 is 4-(4-chlorophenyl)benzyl or 4-(4-chlorobenzyloxy)benzyl.
The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention. In one preferred embodiment, the pharmaceutically acceptable carrier comprises an aqueous cyclodextrin solution. Preferably, the cyclodextrin is hydroxypropyl-xcex2-cyclodextrin or sulfobutyl ether xcex2-cyclodextrin. More preferably, the cyclodextrin is hydroxypropyl-xcex2-cyclodextrin.
The compounds of the invention are highly effective antibacterial agents. Accordingly, the invention also provides a method of treating a mammal having a bacterial disease, comprising administering to the mammal a therapeutically effective amount of a compound of the invention. The invention also provides a method of treating a mammal having a bacterial disease, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the invention.
The invention also provides processes and intermediates useful for preparing compounds of the invention, which processes and intermediates are described further herein.
The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a bacterial disease in a mammal.
Preferred compounds of the invention are the compounds of formula II shown in Table I below wherein R19 and R21 are each hydrogen.
Another preferred group of compounds of the invention are C-terminus polyacid derivatives of the glycopeptide antibiotic A82846B (also known as chloroorienticin A oy LY264826). See for example R. Nagarajan et al., J. Org. Chem., 1988, 54, 983-986; and N. Tsuji et al., J. Antibiot., 1988, 41, 819-822. The structure of this glycopeptide is similar to vancomycin, except A82846B contains an additional amino sugar (i.e. 4-epi-vancosamine attached at the R2 position in formula I.) and further contains 4-epi-vancosamine in place of vancosamine in the disaccharide moiety attached at the R1 position in formula I. For example, a preferred group of compounds are N-alkylated derivatives of A82846B having a polyacid group at the C-terminus. N-alkylated derivatives of A82846B are known in the art and are described, for example, in U.S. Pat. No. 5,840,684. C-Terminus polyacid derivatives of these compounds can readily be prepared using the procedures described herein.
A particularly preferred group of compounds of the invention are A82846B derivatives having a 4-(4-chlorophenyl)benzyl group or a 4-(4-chlorobenzyloxy)benzyl group attached at the amino group of the 4-epi-vancosamine of the disaccharide moiety and having a group substituted at the C-terminus that comprises two or more carboxy group. Preferred polycarboxy substituents for A82846B derivatives include a nitrogen-linked aspartic acid, a nitrogen linked glutamic acid, and a nitrogen-linked radical of formula III as described herein.